What turns CREB on? And off? And why does it matter?

Steven, André; Friedrich, Michael W.; Jank, Paul; Heimer, Nadine; Budczies, Jan; Denkert, Carsten; Seliger, Barbara

doi:10.1007/s00018-020-03525-8

Cited by 133 publications

(113 citation statements)

References 224 publications

(188 reference statements)

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“…As a second messenger, cAMP is responsible for activation of the protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac) and ion gated channel protein [ 7 ]. As one of the target proteins of PKA, cAMP response element binding protein (CREB) is an important transcription factor that regulates the expression of several genes including oncogenes c-Jun and cyclin D1 [ 8 ]. Notably, cAMP–PKA–CREB signaling has both tumor-suppressive and tumot-promoting effects on cancer, depending on the tumor types and context.…”

Section: Introductionmentioning

confidence: 99%

Complex roles of cAMP–PKA–CREB signaling in cancer

et al. 2020

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Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

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Section: Introductionmentioning

confidence: 99%

Complex roles of cAMP–PKA–CREB signaling in cancer

et al. 2020

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“…The upregulation of PKA activity in HCC cells by aspirin indicates that AMPK-mediated PKA activation outweighs PKA inactivation resulting from COX inhibition if the latter situation does happen. CREB has been identified to promote tumor progression and to be associated with the overall survival and therapy response of patients with many types of cancer, while it may be tumor-suppressive in some types of cancer [ 45 , 46 , 47 ]. From a therapeutic perspective, the induction of PKA and CREB/ATF1 activation by aspirin and AMPK may be a disadvantage for treating many cancer types.…”

Section: Discussionmentioning

confidence: 99%

Blockade of AMPK-Mediated cAMP–PKA–CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma

Zhang

Yang

Wang

et al. 2021

Cancers

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Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin’s anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA–CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA–CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC.

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“…Thus, the DNA binding site for CREB, the cyclic AMP-response element, has also been called the Ca 2+ -responsive element [30]. CREB is a substrate for multiple protein kinases including the cAMP-dependent protein kinase PKA, the Ca 2+ /calmodulin regulated protein kinase CaMKIV, mitogen and stressinduced protein kinase (MSK), MAP kinase kinase 6, protein kinase B, ribosomal S6 kinase and others [32][33][34][35]. binding protein).…”

Section: Ca 2+ -Responsive Transcription Factorsmentioning

confidence: 99%

Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

Thiel

Schmidt

Rößler

2021

Cells

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Ca2+ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca2+ concentration upon stimulation. The elevated Ca2+ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca2+ at different locations in the cell. Ca2+ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca2+ ions. A major function of the rise in intracellular Ca2+ is the change of the genetic expression pattern of the cell via the activation of Ca2+-responsive transcription factors. It has been proposed that Ca2+-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca2+. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca2+ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca2+ induces an intracellular signaling cascade, involving the activation of the Ca2+/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca2+/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca2+ concentration in the cytoplasm and the nucleus, the role of Ca2+ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca2+ signaling and gene expression.

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What turns CREB on? And off? And why does it matter?

Cited by 133 publications

References 224 publications

Complex roles of cAMP–PKA–CREB signaling in cancer

Complex roles of cAMP–PKA–CREB signaling in cancer

Blockade of AMPK-Mediated cAMP–PKA–CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma

Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

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